PROTEOGLYCANS IN GROWTH FACTOR SIGNALING AND DEVELOPMENT

生长因子信号传导和发育中的蛋白聚糖

• 批准号: 6683754
• 负责人: SCOTT B SELLECK
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683754
• 关键词: Drosophilidae; arthropod genetics; axon; biological signal transduction; cell cycle; cell growth regulation; developmental genetics; developmental neurobiology; gene expression; growth factor receptors; molecular dynamics; mucopolysaccharides; neurogenesis; protein structure function; proteoglycan; site directed mutagenesis; synaptogenesis; tissue /cell culture; transmission electron microscopy; tumor suppressor proteins

DESCRIPTION (PROVIDED BY APPLICANT): Cell surface proteoglycans serve critical functions in the tissue-selective regulation of growth factor signaling. Current evidence indicates that proteoglycans control the assembly of growth factor ligand-receptor complexes at the cell surface. Glypicans represent one family of integral membrane proteoglycans, characterized by a GPIlinkage to the outer leaflet of the plasma membrane and heparan sulfate modification. One human glypican, GPC3, is remarkable for its role in the regulation of body size and tumor development. Glypicans are also widely expressed in the vertebrate nervous system, although nothing is known about their function in this tissue. The long term goals of this project are to understand the diverse molecular functions of glypicans, including their involvement in growth control, tumor suppression, and nervous system development using genetic and molecular tools available in the fruitfly, Drosophila melanogaster. We have identified mutations affecting both of the two glypican encoding genes in Drosophila, division abnormally delayed (daily), and daily-like (dly). Our recent studies have shown that daily and daily-like affect tissue and cell growth at least in part by regulation of Insulin-like growth factor signaling. We have also uncovered axonogenesis defects in the central nervous system of dly mutants. Finally, we have determined that glycosaminoglycan biosynthesis is critical for assembly of the neuromuscular synapse in Drosophila. These observations serve as the basis of our specific aims: Aim 1. Determine the molecular activity of daily and daily-like in cell and tissue growth control. Aim 2. Examine the molecular mechanisms of Daily and Daily-like mediated inhibition of insulin responses in Drosophila S2 cells. Aim 3. Determine the molecular and cellular basis of embryonic axon projection defects in daily-like mutants. Aim 4. Establish the molecular basis for glypican and glycosaminoglycan function in synapse assembly.

描述（由申请人提供）：细胞表面蛋白聚糖服务至关重要 生长因子信号传导组织选择性调节的功能。 当前的证据表明蛋白聚糖控制着生长的组装 因子配体受体复合物在细胞表面。 Glypicans代表一个 整体膜蛋白聚糖的家族，其特征是Gpilinkage 质膜和硫酸乙酰肝素修饰的外小叶。一 人类Glypican，GPC3，以其在体型调节中的作用而闻名 和肿瘤发育。 Glypicans也在脊椎动物中广泛表达 神经系统，尽管对它们在该组织中的功能一无所知。 该项目的长期目标是了解不同的分子 糖剂的功能，包括它们参与生长控制，肿瘤 使用遗传和分子工具抑制和神经系统的发展 可在果蝇，果蝇果蝇中提供。 我们已经确定了影响两个编码基因的两个Glypican的突变 在果蝇中，分裂异常延迟（每日），每天（dly）。我们的 最近的研究表明，每天和每天都会影响组织和细胞 至少部分通过胰岛素样生长因子信号传导而生长。 我们还发现了中枢神经系统中的轴突发生缺陷 乳头突变体。最后，我们确定糖胺聚糖生物合成是 果蝇中神经肌肉突触的组装至关重要。这些 观察是我们特定目标的基础：目标1。确定 细胞和组织生长控制中日常和每天样的分子活性。 目标2。检查日常和每日介导的分子机制 果蝇S2细胞中胰岛素反应的抑制。目标3。确定 胚胎轴突投影缺陷的分子和细胞基础在类似 突变体。目标4。建立Glypican和 突触组件中的糖胺聚糖功能。